Ethanol consumed by a person is removed from the bloodstream, in large part, in a two-step pathway in which ethanol is oxidized by alcohol dehydrogenase to acetaldehyde, that is in turn quickly metabolized into acetic acid by aldehyde dehydrogenase subtype 2 (ALDH2), a mitochondrial liver enzyme (see FIG. 1). Acetaldehyde acts as a toxin in the human body, and is linked to acute symptoms such as facial flushing, tachycardia, shortness of breath, dizziness, nausea, vomiting and headache (Inoue et al., Alcoholism: Clinical and Experimental Research 1984, 8, 319-322; Inoue et al., Japan. J. Pharmacol. 1985, 38, 43-48), as well as to increased long-term health risks for cancers of the upper digestive tract, breast cancer, liver disease, Alzheimer's disease, asthma, hypertension and myocardial infarction (Enomoto et al., Hepatology 1991, 13, 1071-5; Takada et al., Alcohol. 1994, 29, 719-27; Chao et al., Hepatology 1994, 19, 360-6; Yamauchi et al. Hepatology 1995, 22, 1136-42; Yokoyama et al., Carcinogenesis. 2001 22(3), 433-439; Ohsawa et al., J. Hum. Genet. 2003, 48, 404-409; Visapää et al., Gut 2004, 53, 871-876; and references cited therein).
A significant portion of the human population is “ALDH2 deficient.” For example, East Asian populations carry a variant allele of ALDH2 (ALDH2*2) that encodes for an enzyme where a glutamic acid at position 487 is substituted with lysine (K487 ALDH2; Chen et al., Am. J. Hum. Genet. 1999, 65(3), 795-807). The K487 ALDH2 enzyme is associated with reduced or absent enzyme activity and increased enzyme turnover (Crabb et al., J. Clin. Invest. 1989, 83, 314-6; Xiao et al., J. Clin. Invest. 1996, 98, 2027-32; Wall et al., Annals of Internal Medicine 1997, 127(5), 376-379). The ALDH2*2 allele is dominant, such that persons who are both heterozygotes and homozygotes for the ALDH2*2 allele are deficient in ALDH2 activity (Crabb et al., J. Clin. Invest. 1989, 83, 314-6). People who express the ALDH2*2 allele exhibit alcohol-related sensitivity, for example, facial flushing, tachycardia, etc., as well as high blood acetaldehyde levels, when drinking small portions of ethanol (Bosron et al., Hepatology 1986, 6, 502-510; Goedde et al., Hum. Genet. 1992, 88, 344-346; Xiao et al., J. Clin. Invest. 1995, 96, 2180-2186). Moreover, people who express the ALDH2*2 allele also exhibit increased long-term health risks for cancers of the upper digestive tract, breast cancer, liver disease, Alzheimer's disease, hypertension and myocardial infarction (Yokoyama et al., Carcinogenesis. 2001 22(3), 433-439; Ohsawa et al., J. Hum. Genet. 2003, 48, 404-409).
Also prevalent in East Asian populations is a variant allele of alcohol dehydrogenase subtype 2 (ADH2*2) that encodes for an enzyme where an arginine at position 47 is substituted with histidine (R47H ADH2; Matsuo et al., Carcinogenesis 2006, 27(5), 1018-1023; Tamakoshi et al., Alcohol 2003, 38, 407-410). The R47H ADH2 enzyme is “superactive,” exhibiting a Vmax about 40 times higher than the less active R47 ADH2 enzyme encoded by the more common allele (ADH2*1) (Bosron et al., Hepatology 1986, 6, 502-510; Yoshida et al., Prog. Nucleic Acid Res. Mol. Biol. 1991, 40, 255-287). The ADH2*2 allele is associated with the accumulation of acetaldehyde, in that people who express the ADH2*2 allele experience an increase in the steady-state concentration of blood or intrahepatic acetaldehyde in their bodies when they drink alcohol (Crabb et al., Proc. Nutr. Soc. 2004, 63(1), 49-63).
A recognized ADH inhibitor, 4-methylpyrazole (also known as fomepizole or 4-MP), has been approved by the U.S. Food and Drug Administration for the treatment of ethylene glycol or methanol poisoning. See, e.g., Scalley et al., American Family Physician 2002, 66, 807-812. As a treatment for ethylene glycol or methanol poisoning, the administration of 4-MP generally requires intravenous infusion under the supervision of a doctor in relatively large doses, e.g., 50 mg/kg or more over time (a 15 mg/kg loading dose given intravenously over 30 minutes, followed by 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours; see Casavant, Pediatrics 2001, 107(1), 170). However, administration of such large doses of 4-MP itself has been reported to cause side effects similar to ALDH2 deficiency including flushing, headache and nausea. See Jacobsen et al., Alcoholism: Clinical and Experimental Research 1988, 12, 516-522. Further, high doses of 4-MP inhibit ADH activity to an extent that human subjects treated with 4-MP can have much higher blood ethanol concentrations than when not treated with 4-MP, leading to relatively lengthy periods of time during which the subject is under the influence of ethanol. See Jacobsen et al., Alcoholism: Clinical and Experimental Research 1996, 20, 804-809.
4-MP has been administered as an “alcohol metabolism enhancer” to treat the symptoms of increased aldehyde accumulation in “alcohol intolerant persons.” See, e.g., Japanese Unexamined Patent Application Publication No. S57-106620. However, such administration has not been shown to be consistently helpful for all alcohol intolerant persons. As explained above, alcohol intolerance persons are members of genetic subpopulations which express different polymorphisms of the ALDH2 and ADH2 genes. These polymorphisms result in different alcohol-related sensitivities and/or to different steady-state acetaldehyde concentrations in alcohol intolerant persons when they drink alcohol. Accordingly, a dose of 4-MP found to be helpful to treat one genetic subpopulation of alcohol intolerance persons may not be equally helpful, or may even be ineffective, to treat another genetic subpopulation of alcohol intolerance persons.
What remains to be determined are solutions to address the adverse consequences of acetaldehyde accumulation in those subpopulations of alcohol intolerant persons that express specific polymorphisms of the ALDH2 and ADH2 genes. Preferably, such solutions will minimally impact the ethanol elimination rate and thereby avoid the consequence of having relatively lengthy periods of time during which the subject is under the influence of ethanol, and avoid the undesirable side-effects associated with higher doses of 4-MP.